The overall goal of this project is to understand predictors of the atherogenic phenotype of lipoprotein (a), [Lp(a)], and underlying mechanisms for uptake and accumulation of this atherogenic lipoprotein in the vessel wall. Lp(a) is an independent cardiovascular risk factor with extensive heterogeneity. Apo(a) is heterogeneous with respect to gene and molecular size, and apo(a) size variability is an important predictor of Lp(a). We and others have identified high levels of Lp(a) with small apo(a) size as an atherogenic phenotype. As the Lp(a) plasma level in any individual represents a sum of two different size apo(a) particle concentrations with potentially different atherogenicity, cardiovascular risk may optimally be assessed by determination of allele- specific apo(a) levels, i.e. the amount of Lp(a) associated with each apo(a) size allele. A key foundation to studies on Lp(a) is the ability to determine apo(a) allele sizes and allele-specific apo(a) levels. We have determined predictors of allele-specific levels and found that allele-specific apo(a) levels are associated with the size and expression of the other apo(a) size allele in a genotype for both African Americans and Caucasians. Further, size of the other allele and homozygosity for the 8 allele of a pentanucleotide repeat polymorphism (PNR) explained the difference between African Americans and Caucasians in allele-specific levels of small, atherogenic apo(a). In the proposed studies, building on our extensive experience and strength in the Lp(a) field, we propose a thematically linked group of projects that will provide integrated information on Lp(a) atherogenicity. We hypothesize: (Aim 1) that allele-specific Lp(a) levels are subject to allelic interactions, where size and expression of one allele affect the allele-specific levels of the other allele;(Aim 2) that Lp(a) with small size apo(a) is more avidly associated with the vessel wall compared to both apo(a) with large size apo(a) and LDL, and (Aim 3) that Lp(a) with small size apo(a) has different scavenger potential for oxidatively modified LDL than Lp(a) with large size apo(a). To minimize genetic variability between individuals and to address ethnic variability, we will focus on family studies and recruit families from two different ethnic groups: African Americans and Caucasians. Taken together, we expect that information obtained in this proposal will help us understand apo(a) allelic interaction, underlying mechanisms for the atherogenic phenotype of Lp(a), and its role in cardiovascular disease. In addition, we hope that our results will provide a framework for approaches to influence Lp(a) in clinical settings. PUBLIC HEALTH RELEVANCE: Lipoprotein(a) is an inherited risk factor for heart disease and stroke. Hardly anything is known about how Lipoprotein(a) causes disease and there are no established treatment guidelines to help prevent disease caused by this factor. The proposal aims to understand which inherited factors affect Lipoprotein(a) and how this factor causes disease. The results will be important to design treatments.